Variants In ABCA7 Research Articles

ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer’s disease through BDNF/NGFR signaling

Genetic variants in ABCA7, an Alzheimer's disease (AD)-associated gene, elevate AD risk, yet its functional relevance to the etiology is unclear. We generated a CRISPR-Cas9-mediated abca7 knockout zebrafish to explore ABCA7's role in AD. Single-cell transcriptomics in heterozygous abca7+/- knockout combined with Aβ42 toxicity revealed that ABCA7 is crucial for neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), and nerve growth factor receptor (NGFR) expressions, which are crucial for synaptic integrity, astroglial proliferation, and microglial prevalence. Impaired NPY induction decreased BDNF and synaptic density, which are rescuable with ectopic NPY. In induced pluripotent stem cell-derived human neurons exposed to Aβ42, ABCA7-/- suppresses NPY. Clinical data showed reduced NPY in AD correlated with elevated Braak stages, genetic variants in NPY associated with AD, and epigenetic changes in NPY, NGFR, and BDNF promoters linked to ABCA7 variants. Therefore, ABCA7-dependent NPY signaling via BDNF-NGFR maintains synaptic integrity, implicating its impairment in increased AD risk through reduced brain resilience.

In vivo validation of late-onset Alzheimer's disease genetic risk factors.

Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics. A novel approach to validate genetic risk factors for late-onset AD (LOAD) is presented. LOAD risk variants were knocked in to conserved mouse loci. Variant effects were assayed by transcriptional analysis. Risk variants in Abca7, Mthfr, Plcg2, and Sorl1 loci modeled molecular signatures of clinical disease. This approach should generate more translationally relevant animal models.

The ABC's of Alzheimer risk gene ABCA7.

Alzheimer's disease (AD) is a growing problem worldwide. Since ABCA7's identification as a risk gene, it has been extensively researched for its role in the disease. We review its recently characterized structure and what the mechanistic insights teach us about its function. We furthermore provide an overview of identified ABCA7 mutations, their presence in different ancestries and protein domains and how they might cause AD. For ABCA7 PTC variants and a VNTR expansion, haploinsufficiency is proposed as the most likely mode-of-action, although splice events could further influence disease risk. Overall, the need to better understand expression of canonical ABCA7 and its isoforms in disease is indicated. Finally, ABCA7's potential functions in lipid metabolism, phagocytosis, amyloid deposition, and the interplay between these three, is described. To conclude, in this review, we provide a comprehensive overview and discussion about the current knowledge on ABCA7 in AD, and what research questions remain. HIGHLIGHTS: Alzheimer's risk-increasing variants in ABCA7 can be found in up to 7% of AD patients. We review the recently characterized protein structure of ABCA7. We present latest insights in genetics, expression patterns, and functions of ABCA7.

The Abca7V1613M variant reduces Aβ generation, plaque load, and neuronal damage.

Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD). CRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed. Abca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aβ) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aβ-associated inflammation, gliosis, and neuronal damage. Overall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aβ pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology. ABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.

Modeling Late-Onset Alzheimer's Disease in Mice

As part of our participation in the Model-AD consortium, the UCI group has developed at least 12 novel mouse models that are relevant to studying the mechanisms underlying late-onset Alzheimer's disease (LOAD). These new models include variants in Abca7, Clu, Picalm, and Trem2. Modeling LOAD is hampered by the subtle effects imparted by the GWAS variants versus the much stronger phenotypic effects imparted by autosomal dominant AD mutations. We have successfully built a platform mouse in which the Aβ sequence has been humanized, and we found that wildtype-hAβ is sufficient to induce synaptic deficits and loss and accelerate the formation of astrocyte-associated Periodic Acid Schiff granules, normally associated with aging. We are actively introducing human tau alleles into these platform mice. Our strategy is to couple the humanizing of critical AD genes (APP, tau) with GWAS variants (Abca7, Clu, Picalm,) to better assess the impact that these alleles have on the phenotype. Modeling late-onset Alzheimer's disease represents a significant challenge, but success will likely yield substantial insights into disease mechanisms and advance drug discovery and evaluation efforts.

Novel mouse models of late‐onset Alzheimer’s disease

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) Consortium was established to generate and characterize more translatable animal models for late‐onset Alzheimer’s disease (LOAD) based on human genetic risk variants. While numerous genetic risk loci for LOAD have been identified, few have been experimentally verified in vivo and in many cases the risk variants have not been validated. The development of new models incorporating LOAD genetic risk should improve our understanding of disease mechanisms and improve preclinical testing of potential therapeutics.MethodCoding and non‐coding LOAD risk variants were prioritized based on human data sets, with the goal of targeting diverse pathways (e.g., neuroinflammation, vascular risk, metabolic function, lipid homeostasis). Risk variants in Abca7, Adamts4, Bin1, Erc2, Mthfr, Mtmr4, Plcg2, Ptk2b, Slc6a17, Snx1, Sorl1 and other loci were engineered into mouse models expressing humanized APOE4 and the Trem2*R47H risk variant; in more recent models, a humanized Abeta allele was also included. A novel transcriptomic panel, based on clinical LOAD samples (Preuss et al, 2020) was used to evaluate how well each model replicated clinical transcriptomic changes with disease. Models were aligned to ROSMAP clinical subtypes.ResultWe have identified specific human AD‐related pathways disrupted in an age‐dependent manner in these novel mouse models. Specifically, mouse models carrying human AD risk variants Abca7*A1527G, Mthfr*C677T, and Plcg2*M28L exhibited transcriptomics changes similar to those seen in LOAD patients. Most models could be readily matched to either the inflammatory or non‐inflammatory subtype.ConclusionWe have prioritized mouse models expressing LOAD risk variants in Abca7, Mthfr, and Plcg2 for comprehensive phenotyping using clinically relevant measures including transcriptomics and proteomics, biomarkers, neuropathology and in vivo imaging at advanced ages (24 months). Ongoing projects will use human data to guide how to combine alleles to create models that match multi‐omic signatures of AD subtypes and test the effects of environmental risk factors such as high‐fat diet. Through this effort we aim to develop improved models for testing targeted therapeutics.

Interaction Analysis Reveals Complex Genetic Associations with Alzheimer's Disease in the CLU and ABCA7 Gene Regions.

Sporadic Alzheimer's disease (AD) is a polygenic neurodegenerative disorder. Single-nucleotide polymorphisms (SNPs) in multiple genes (e.g., CLU and ABCA7) have been associated with AD. However, none of them were characterized as causal variants that indicate the complex genetic architecture of AD, which is likely affected by individual variants and their interactions. We performed a meta-analysis of four independent cohorts to examine associations of 32 CLU and 50 ABCA7 polymorphisms as well as their 496 and 1225 pair-wise interactions with AD. The single SNP analyses revealed that six CLU and five ABCA7 SNPs were associated with AD. Ten of them were previously not reported. The interaction analyses identified AD-associated compound genotypes for 25 CLU and 24 ABCA7 SNP pairs, whose comprising SNPs were not associated with AD individually. Three and one additional CLU and ABCA7 pairs composed of the AD-associated SNPs showed partial interactions as the minor allele effect of one SNP in each pair was intensified in the absence of the minor allele of the other SNP. The interactions identified here may modulate associations of the CLU and ABCA7 variants with AD. Our analyses highlight the importance of the roles of combinations of genetic variants in AD risk assessment.

Rare missense mutations in ABCA7 might increase Alzheimer\u2019s disease risk by plasma membrane exclusion

The adenosine triphosphate–binding cassette subfamily A member 7 gene (ABCA7) is associated with Alzheimer’s disease (AD) in large genome-wide association studies. Targeted sequencing of ABCA7 suggests a role for rare premature termination codon (PTC) mutations in AD, with haploinsufficiency through nonsense-mediated mRNA decay as a plausible pathogenic mechanism. Since other classes of rare variants in ABCA7 are poorly understood, we investigated the contribution and pathogenicity of rare missense, indel and splice variants in ABCA7 in Belgian AD patient and control cohorts. We identified 8.36% rare variants in the patient cohort versus 6.05% in the control cohort. For 10 missense mutations identified in the Belgian cohort we analyzed the pathogenetic effect on protein localization in vitro using immunocytochemistry. Our results demonstrate that rare ABCA7 missense mutations can contribute to AD by inducing protein mislocalization, resulting in a lack of functional protein at the plasma membrane. In one pedigree, a mislocalization-inducing missense mutation in ABCA7 (p.G1820S) co-segregated with AD in an autosomal dominant inheritance pattern. Brain autopsy of six patient missense mutation carriers showed typical AD neuropathological characteristics including cerebral amyloid angiopathy type 1. Also, among the rare ABCA7 missense mutations, we observed mutations that affect amino acid residues that are conserved in ABCA1 and ABCA4, of which some correspond to established ABCA1 or ABCA4 disease-causing mutations involved in Tangier or Stargardt disease.

Transcript levels in plasma contribute substantial predictive value as potential Alzheimer's disease biomarkers in African Americans.

SummaryBackgroundAfrican Americans (AA) remain underrepresented in Alzheimer's disease (AD) research, despite the prevalence of AD being double in AA compared to non-Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer's Disease Studies (FCA3DS), focusing on the identification of genetic risk factors and novel plasma biomarkers.MethodUtilizing FCA3DS whole exome sequence (WES) and plasma RNA samples from AD cases (n=151) and cognitively unimpaired (CU) elderly controls (n=269), we have performed differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom nanoString® panel. We designed this panel to measure, in plasma, cell-free mRNA (cf-mRNA) levels of AD-relevant genes.FindingsAssociation with higher plasma CLU in CU vs. AD remained significant after Bonferroni correction. Study-wide significant eQTL associations were observed with 105 WES variants in cis with 22 genes, including variants in genes previously associated with AD risk in AA such as ABCA7 and AKAP9. Results from this plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that are significantly associated with lower and higher plasma mRNA levels of these genes, respectively. Receiver operating characteristic analysis of age, sex APOE-ε4 dosage, CLU, APP, CD14, ABCA7, AKAP9 and APOE mRNA levels, and ABCA7 and AKAP9 eQTLs, achieved 77% area under the curve to discriminate AD vs. CU, an 8% improvement over a model that only included age, sex and APOE-ε4 dosage.InterpretationIncorporating plasma mRNA levels could contribute to improved predictive value of AD biomarker panels.FundingThis work was supported by the National Institute on Aging [RF AG051504, U01 AG046139, R01 AG061796 to NET; P30 AG062677 to JAL and NGR]; Florida Health Ed and Ethel Moore Alzheimer's Disease grants [5AZ03 and 7AZ17 to NET; 7AZ07 to MMC; 8AZ08 to JAL].

Clinical Deep Phenotyping of ABCA7 Mutation Carriers.

Background and ObjectivesPutative loss-of-function (pLOF) ABCA7 variants that increase Alzheimer disease (AD) risk were identified; however, deep phenotypic characterization of these variants in mutation carriers is limited. We aimed to obtain deep clinical phenotypes of ABCA7 pLOF mutation carriers from a large retrospectively reviewed series.MethodsGenotypes were determined for 5,353 individuals evaluated at Mayo Clinic for 6 reported ABCA7 pLOF variants (p.E709fs, p.Trp1214X, p.L1403fs, c.4416+2T>G, p.E1679X, and c.5570+5G>C). Medical records of 100 mutation carriers were reviewed for demographics, clinical phenotypes, and diagnoses. Eleven mutation carriers had autopsy-based neuropathologic diagnoses.ResultsWe confirmed that ABCA7 pLOF mutations confer AD risk in our series of 2,495 participants with AD and 2,858 cognitively unaffected participants. Clinical review of 100 mutation carriers demonstrated phenotypic variability of clinical presentations with both memory and nonmemory cognitive impairment and a subset presenting with motor symptoms. There was a wide range of age at onset of cognitive symptoms (ages 56–92 years, mean = 75.6). Ten of the 11 autopsied mutation carriers had AD neuropathology. ABCA7 pLOF mutation carriers had higher rates of depression (41.6%) and first-degree relatives with cognitive impairment (38.1%) compared with the general population.DiscussionOur study provides a deep clinical review of phenotypic characteristics of mutation carriers for 6 ABCA7 pLOF mutations. Although memory impairment was the most common initial symptom, nonmemory cognitive and/or motor symptoms were present in a substantial number of mutation carriers, highlighting the heterogeneity of clinical features associated with these mutations. Likewise, although AD neuropathology is the most common, it is not the only autopsy-based diagnosis. Presence of earlier ages at onset, higher rates of depression, and first-degree relatives with cognitive impairment among mutation carriers suggest that these genetic variants may have more aggressive clinical features than AD in the general population. This deep phenotyping study of ABCA7 pLOF mutation carriers provides essential genotype-phenotype correlations for future precision medicine approaches in the clinical setting.

Associations of risk genes with onset age and plasma biomarkers of Alzheimer's disease: a large case-control study in mainland China.

Most genetic studies concerning risk genes in Alzheimer's disease (AD) are from Caucasian populations, whereas the data remain limited in the Chinese population. In this study, we systematically explored the relationship between AD and risk genes in mainland China. We sequenced 33 risk genes previously reported to be associated with AD in a total of 3604 individuals in the mainland Chinese population. Common variant (MAF ≥ 0.01) based association analysis and gene-based (MAF < 0.01) association test were performed by PLINK 1.9 and Sequence Kernel Association Test-Optimal, respectively. Polygenic risk score (PRS) was calculated, and receiver operating characteristic curve (AUC) was computed. Plasma Aβ42, Aβ40, total tau (T-tau), and neurofilament light chain (NFL) were tested in a subgroup, and their associations with PRS were conducted using the Spearman correlation test. Six common variants varied significantly between AD patients and cognitively normal controls after the adjustment of age, gender, and APOE ε4 status, including variants in ABCA7 (n = 5) and APOE (n = 1). Among them, four variants were novel and two were reported previously. The AUC of PRS was 0.71. The high PRS was significantly associated with an earlier age at onset (P = 4.30 × 10-4). PRS was correlated with plasma Aβ42, Aβ42/Aβ40 ratio, T-tau, and NFL levels. Gene-based association test revealed that ABCA7 and UNC5C reached statistical significance. The common variants in APOE and ABCA7, as well as rare variants in ABCA7 and UNC5C, may contribute to the etiology of AD. Moreover, the PRS, to some extent, could predict the risk, onset age, and biological changes of AD.

Association of the top 20 Alzheimer's disease risk genes with [18F]flortaucipir PET.

IntroductionWe previously reported genetic associations of the top Alzheimer's disease (AD) risk alleles with amyloid deposition and neurodegeneration. Here, we report the association of these variants with [18F]flortaucipir standardized uptake value ratio (SUVR).MethodsWe analyzed the [18F]flortaucipir scans of 352 cognitively normal (CN), 160 mild cognitive impairment (MCI), and 54 dementia (DEM) participants from Alzheimer's Disease Neuroimaging Initiative (ADNI)2 and 3. We ran step‐wise regression with log‐transformed [18F]flortaucipir meta—region of interest SUVR as the outcome measure and genetic variants, age, sex, and apolipoprotein E (APOE) ε4 as predictors. The results were visualized using parametric mapping at familywise error cluster‐level–corrected P < .05.Results APOE ε4 showed significant (P < .05) associations with tau deposition across all disease stages. Other significantly associated genes include variants in ABCA7 in CN, CR1 in MCI, BIN1 and CASS4 in MCI and dementia participants.DiscussionWe found significant associations to tau deposition for ABCA7, BIN1, CASS4, and CR1, in addition to APOE ε4. These four variants have been previously associated with tau metabolism through model systems.

Plasma transcript profiling identifies significant differentially expressed genes and expression of quantitative trait loci in African Americans

AbstractBackgroundAfrican Americans (AA) remain underrepresented in Alzheimer’s disease (AD) research, despite the prevalence of AD being ∼2X higher in this population compared to non‐Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer’s Disease Studies (FCA3DS), focusing primarily on the identification of genetic risk factors and novel plasma biomarkers.MethodUtilizing plasma samples from FCA3DS AD cases (n=158) and cognitively unimpaired elderly controls (n=272), we have performed differential gene expression (DEG) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom NanoString® panel that we have designed to measure transcript levels in plasma of genes relevant to AD. Transcript counts were determined using the NanoString® nCounter system, following manufacturer’s protocols. Transcript counts from 43 of the 50 customs assays passed pre‐established quality control thresholds and were utilized for the DEG and eQTL analyses. Our published FCA3DS whole exome sequence (WES) data was utilized for the eQTL analyses. Linear mixed models adjusted for relevant biological and technical covariates were implemented with the lme4 package in R software (v3.6.2) for the DEG and eQTL analyses.ResultAn association with higher plasma CLU in controls compared to AD remained significant after Bonferroni correction for the 43 transcripts tested. The eQTL analysis revealed significant association (FDR q‐value&lt;0.05) with 105 WES variants in cis with 22 of 43 genes tested, including variants in genes previously associated with AD risk in AA. ConclusionThe results from this AA plasma eQTL analysis revealed ABCA7 variants that are significantly associated with lower plasma ABCA7 transcript levels. One of the significant plasma ABCA7 eQTLs was previously shown by our group to be associated with increased AD risk in AA, suggesting that this may be a functional eQTL underlying the risk of AD in AA. The association of higher levels of CLU transcript in plasma from controls compared to AD is in line with results published by others which showed that higher baseline concentration of clusterin protein in plasma was associated with slower rates of brain atrophy. These results support plasma transcripts as novel endophenotypes in AD biomarker studies.

Transcript Levels in Plasma Contribute Substantial Predictive Value as Potential Alzheimer's Disease Biomarkers in African Americans

Background: African Americans (AA) remain underrepresented in Alzheimer’s disease (AD) research, despite the prevalence of AD being double in AA compared to non-Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer’s Disease Studies (FCA3DS), focusing on the identification of genetic risk factors and novel plasma biomarkers. Method: Utilizing FCA 3 DS whole exome sequence (WES) and plasma RNA samples from AD cases (n=151) and cognitively unimpaired (CU) elderly controls (n=269), we have performed differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom nanoString® panel. We designed this panel to measure, in plasma, cell-free mRNA (cf-mRNA) levels of AD-relevant genes. Findings: Association with higher plasma CLU in CU vs. AD remained significant after Bonferroni correction. Study-wide significant eQTL associations were observed with 105 WES variants in cis with 22 genes, including variants in genes previously associated with AD risk in AA such as ABCA7 and AKAP9. Results from this plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that are significantly associated with lower and higher plasma mRNA levels of these genes, respectively. ROC analysis of age, sex APOE-e4 dosage, CLU, APP, CD14, ABCA7, AKAP9 and APOE mRNA levels, and ABCA7 and AKAP9 eQTLs, achieved 77% AUC to discriminate AD vs. CU, an 8% improvement over a model that only included age, sex and APOE-e4 dosage. Interpretation: Incorporating plasma mRNA levels could contribute to improved predictive value of AD biomarker panels. Funding: National Institute on Aging, Florida Health Ed and Ethel Moore Alzheimer’s Disease grants. Declaration of Interest: None to declare. Ethical Approval: Informed consent and approval by the Mayo Clinic Institutional Review Board was obtained.

Role of Genetic Variation in ABC Transporters in Breast Cancer Prognosis and Therapy Response.

Breast cancer is the most common cancer in women in the world. The role of germline genetic variability in ATP-binding cassette (ABC) transporters in cancer chemoresistance and prognosis still needs to be elucidated. We used next-generation sequencing to assess associations of germline variants in coding and regulatory sequences of all human ABC genes with response of the patients to the neoadjuvant cytotoxic chemotherapy and disease-free survival (n = 105). A total of 43 prioritized variants associating with response or survival in the above testing phase were then analyzed by allelic discrimination in the large validation set (n = 802). Variants in ABCA4, ABCA9, ABCA12, ABCB5, ABCC5, ABCC8, ABCC11, and ABCD4 associated with response and variants in ABCA7, ABCA13, ABCC4, and ABCG8 with survival of the patients. No association passed a false discovery rate test, however, the rs17822931 (Gly180Arg) in ABCC11, associating with response, and the synonymous rs17548783 in ABCA13 (survival) have a strong support in the literature and are, thus, interesting for further research. Although replicated associations have not reached robust statistical significance, the role of ABC transporters in breast cancer should not be ruled out. Future research and careful validation of findings will be essential for assessment of genetic variation which was not in the focus of this study, e.g., non-coding sequences, copy numbers, and structural variations together with somatic mutations.

Association of rare variants in neurodegenerative genes with familial Alzheimer's disease.

ObjectiveTo investigate the impact of rare variants underlying neurodegenerative‐related genes to familial Alzheimer’s disease (AD).MethodsWe performed targeted sequencing of 277 neurodegenerative‐related genes on probands from 75 Chinese AD families non‐carrying causative mutation of dementia genes. Rare coding variants segregated in families were tested for association in an independent cohort of 506 patients with sporadic AD and 498 cognitively normal controls. East Asians data from the Exome Aggregation Consortium (ExAC) were used as a reference control.ResultsA novel rare variant, P410S of PLD3 was found in an early‐onset AD family. LRRK2 I2012T, a causative mutation of Parkinson’s disease, was identified in another early‐onset AD family. Missense variants in ABCA7 (P143S and A1507T) and CR1(T239M) were significantly associated with familial AD (P = 0.005437, 0.001383, 0.000549), a missense variant in TREM2(S183C) was significantly associated with AD (P = 0.000396) when compared with the East Asian controls in ExAC database. A non‐frameshift variant in FUS (G223del) was frequent in AD cases and significantly associated with familial AD (P = 0.008).InterpretationMultiple rare coding variants of causal and risk neurodegenerative genes were presented in clinically diagnosed AD families that may confer risk of AD. Our data supported that the clinical, pathological, and genetic architectures of AD, PD, and FTD/ALS may overlapping. We propose that targeted sequencing on neurodegenerative‐related genes is necessary for genetically unclear AD families.

NOVEL MODELS OF LATE-ONSET ALZHEIMER’S DISEASE BASED ON GWAS

The Alzheimer's Disease (AD) patient population consists almost entirely (∼98%) of the late-onset form of AD (LOAD); however, most mouse models currently used to develop therapies for AD are based on familial AD (fAD) mutations in APP, PSEN1 or PSEN2. This may contribute to failures moving potential therapies from preclinical models into the clinic. The Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) Center was created to develop, characterize, and distribute more precise preclinical models for LOAD. Because the APOE4 variant and variants at the Trem2 locus are the strongest genetic risk factors for LOAD, we first created a homozygous model expressing humanized APOE4 and the R47H allele of the Trem2 gene. Additional genetic variants were prioritized in loci previously identified by GWAS using data from the IGAP, ADNI, and ADSP projects. These variants have been engineered into the APOE4/Trem2*R47H model to increase the risk of developing AD-like phenotypes. We have created models including SNPs corresponding to risk variants in ABCA7 and MTHFR, and knockouts of mouse Il1rap and Ceacam1. We have also created a humanized APP model by altering the three amino acids that differ between human and mouse Aβ42. In addition, we have created APOE3 and APOE2 variants to serve as controls. We will present validation data including transcriptomics, pathology, and functional assays on the APOE4/Trem2 model; all new models are currently being aged for phenotypic studies, and results will be compared to those from fAD models as well as to clinical data. We have created novel mouse models that express combinations of genetic variants identified in human LOAD patient populations. Our strategy closely integrates human and mouse data, with the aim that these new LOAD models will show a high degree of clinical translatability for preclinical testing of new therapeutic targets. All new models will be made available for both academic and for-profit use from The Jackson Laboratory (www.jax.org/alzheimers ), and all validation data will be shared via the AMP-AD knowledge portal (www.synapse.org/alzheimers ). We seek input and collaborations from the basic research and pharma/biotech communities. For more information see www.model-ad.org.

Rare ABCA7 variants in 2 German families with Alzheimer disease.

ObjectiveThe aim of this study was to identify variants associated with familial late-onset Alzheimer disease (AD) using whole-genome sequencing.MethodsSeveral families with an autosomal dominant inheritance pattern of AD were analyzed by whole-genome sequencing. Variants were prioritized for rare, likely pathogenic variants in genes already known to be associated with AD and confirmed by Sanger sequencing using standard protocols.ResultsWe identified 2 rare ABCA7 variants (rs143718918 and rs538591288) with varying penetrance in 2 independent German AD families, respectively. The single nucleotide variant (SNV) rs143718918 causes a missense mutation, and the deletion rs538591288 causes a frameshift mutation of ABCA7. Both variants have previously been reported in larger cohorts but with incomplete segregation information. ABCA7 is one of more than 20 AD risk loci that have so far been identified by genome-wide association studies, and both common and rare variants of ABCA7 have previously been described in different populations with higher frequencies in AD cases than in controls and varying penetrance. Furthermore, ABCA7 is known to be involved in several AD-relevant pathways.ConclusionsWe conclude that both SNVs might contribute to the development of AD in the examined family members. Together with previous findings, our data confirm ABCA7 as one of the most relevant AD risk genes.

Updated Meta-Analysis of BIN1, CR1, MS4A6A, CLU, and ABCA7 Variants in Alzheimer's Disease.

Genome-wide association studies (GWAS) have associated several genetic variants with late-onset Alzheimer's disease (LOAD), a neurodegenerative disease. Among those, rs3764650 ABCA7, rs6656401 CR1, and rs744373 BIN1 were associated as risk factors for LOAD, while rs11136000 CLU and rs610932 MS4A6A were protective. Recently, several case-control studies have investigated the association of these polymorphisms with AD. However, not all meta-analyses analyzed these variants across different ethnic groups. Therefore, we performed an updated meta-analysis of rs3764650 ABCA7, rs6656401 CR1, rs744373 BIN1, rs11136000 CLU, and rs610932 MS4A6A variants associated with LOAD, considering different ethnic populations. We utilized samples from 38 articles, comprising a total of 24,771 patients and 35,324 controls obtained through the PubMed database. Odds ratios (ORs) with 95% confidence intervals (CI) for polymorphisms were calculated by allelic comparison as an additive genetic model. We validated the risk for LOAD with BIN1 (rs744373), CR1 (rs6656401), and ABCA7 (rs376465), as well as the protective association for MS4A6A (rs610932) and CLU (rs11136000) variants.

ASSOCIATION OF CHOLESTEROL AND CHOLESTEROL METABOLISM GENES WITH COGNITIVE FUNCTION IN A POPULATION ENRICHED FOR A PARENTAL HISTORY OF ALZHEIMER’S DISEASE

APOE ε4 and ABCA7 variants are susceptibility genes for Alzheimer's disease (AD). Both genes are involved in the cholesterol metabolism pathway, and mid-life cholesterol levels are associated with increased risk for AD. The interaction between APOE ε4 and ABCA7has been associated with three cognitive factor scores, Verbal Learning & Memory, Working Memory, and Immediate Memory, in a study of participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a longitudinal study of middle-aged adults enriched for a parental history of AD. As a follow-up to this study, we sought to examine the influence of total serum cholesterol on this interaction effect. Linear mixed models were used to test the influence of total serum cholesterol on the APOE ε4 x ABCA7effect on the three cognitive factor scores (n=778). Each model was adjusted for age, gender, and the top two principal components of ancestry while including random effects for family (siblings) and participant (repeated measures). Continuous serum cholesterol measures were included as a covariate where appropriate. The addition of serum cholesterol to the model did not attenuate the previously reported effect of the APOE ε4 x ABCA7 interaction on the three cognitive factor scores, suggesting serum cholesterol is not in the causal pathway for this association. When stratifying the population by mean total serum cholesterol, the effect of the APOE ε4 x ABCA7 interaction on all three cognitive factor scores differed by tertile and ABCA7SNP. Total serum cholesterol was not found to be in the causal pathway of the APOE ε4 x ABCA7 interaction, but did appear to be a modifier of the interaction effect on the cognitive factor scores. APOE ε4 and ABCA7 genotypes along with cholesterol levels should be considered together when addressing cognitive function in at-risk populations.